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Journal of Cancer Prevention


Cancer prevention research 2005; 10(1): 34-47

Published online March 30, 2005

© Korean Society of Cancer Prevention

Effects of Hepatic Disease on Flow-limited Verapamil Pharmacokinetics in the DMN-induced Hepatic Cirrhotic Rats

Jung-Wook Hong1, Yun-Young Park1, Hai-Dan Yuan1, Hyun-Jin Kim1, Joo-Won Lee1, Ok-Hwa Jhee1,3, Ae-Son Om3, Sang-Koo Lee4, Yun-Sik Lee5, In-Chul Shin1, Min-Ho Lee2 and Ju-Seop Kang1


The purpose of this study was to determine the effect of hepatic disease severities on pharmacokinetics of flow-limited verapamil in dimethylnitrosamine (DMN)-induced cirrhotic rats. Hepatic cirrhotic rats (SD rats, 200∼250 g) were induced by intraperitoneal injection with 1% DMN solution at a dose of 10μg/g by 3 days/week as experimental groups and same dose of saline as control for 4 weeks. The serum verapamil concentrations were quantified at zero, 10 min, 30 min, 1, 2 and 3 hrs after bolus injection of 3 mg/kg of verapamil by a column-switching HPLC method and pharmacokinetic parameters such as Co, MRT, AUC, Vdss, t1/2 (β) and CLp were determined in each group. And then some hepatic tissue was obtained and subjected to analysis of the hepatic 4-hydroxyproline content and were inspected by light microscope after hematoxylin and eosin staining. The serum concentrations and pharmacokinetic parameters such as Co, AUC, MRT and t1/2 (β) were significantly increased (p<0.01) and Vdss and CLp were significantly decreased (p<0.01) in hepatic cirrhotic rats according to DMN-treated period. The 4-hydroxyproline content was also gradually increased propertionally to DMN-treated period. The pharmacokinetic parameters of verapamil were seemed to change gradually to depend on the hepatic fibrotic severity. Therefore, we suggested that flow-limited drug as like verapamil dosage adjustment is necessary according to hepatic function severity. (Cancer Prev Res 10, 34-47, 2005)

Keywords: Flow-limited verapamil, Cirrhosis, HPLC, Pharmacokinetic parameter

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